αα-hub coregulator structure and flexibility determine transcription factor binding and selection in regulatory interactomes

Theisen, Frederik Friis; Salladini, Edoardo; Davidsen, Rikke; Rasmussen, Christina Jo; Staby, Lasse; Kragelund, Birthe B.; Skriver, Karen

doi:10.1016/j.jbc.2022.101963

Cited by 7 publications

(6 citation statements)

References 77 publications

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“…In this study, we asked how activators and repressors may interact with the same TF through the same binding region. Focusing on the DREB2A interaction with Med25 enabled comparison to previous studies with the negative regulator RCD1 and the coactivator TAF4, both of which bind DREB2A through their RST domain 40 . DREB2A interacts with Med25-ACID using a 40-residue region containing two SLiMs.…”

Section: Discussionmentioning

confidence: 99%

“…Bivalency allows high affinity binding and thereby specificity in interactions. However, for the DREB2A:Med25-ACID interaction, the weak secondary binding site and energetic frustration, particularly of the trans bound state, may allow other co-regulators, such as TAF4 40 and RCD1 20 , to bind the RIM and either displace DREB2A from Med25 or participate in ternary complexes (Figure 7A). ID-based molecular competition has been demonstrated for the HIF1⍺ and CITED2 transcription factors in their binding to the TAZ1 domain of CBP as part of the hypoxic response 48 .…”

Section: Discussionmentioning

confidence: 99%

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Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants

Theisen,

Prestel,

Elkjær

et al. 2023

Preprint

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The Arabidopsis thaliana DREB2A transcription factor interacts with the negative regulator RCD1 and the ACID domain of subunit 25 of the transcriptional activator mediator (Med25) to integrate stress signals for gene expression, with elusive molecular interplay. Using biophysical and structural analyses together with high-throughput screening, we revealed a bivalent binding switch in DREB2A containing a novel ACID-binding motif (ABS) and the RCD1-binding motif (RIM). The RIM is lacking in a stress-induced DREB2A splice variant with retained activity. ABS and RIM bound to separate sites on Med25-ACID, and NMR uncovered a structurally heterogeneous complex deriving from a DREB2A-ABS proline residue populating cis- and trans-isomers with remote impact on the RIM. The cis-isomer stabilized an α-helix, while the trans-isomer may introduce energetic frustration facilitating rapid exchange between activators and repressors. Thus, DREB2A uses a post-transcriptionally and post-translationally modulated switch for transcriptional regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants

Theisen,

Prestel,

Elkjær

et al. 2023

Preprint

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“…A recent comparative study of αα-hub domains suggested that the C-terminal region of the At RCD1-RST-binding SliM in DREB2A differentially participates in α-helix formation depending on the biological relevance and biochemical specificity of the interaction 52 . With the results obtained here, this jointly promotes a model in which the RCD1-RST-binding region of DREB2A is divided into an N-terminal helix core with a cap defining and stabilizing the induced α-helix and a C-terminal regulatory region with differential folding depending on the partner (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary fine-tuning of residual helix structure in disordered proteins manifests in complex structure and lifetime

et al. 2023

Self Cite

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Transcription depends on complex networks, where folded hub proteins interact with intrinsically disordered transcription factors undergoing coupled folding and binding. For this, local residual structure, a prototypical feature of intrinsic disorder, is key. Here, we dissect the unexplored functional potential of residual structure by comparing structure, kinetics, and thermodynamics within the model system constituted of the DREB2A transcription factor interacting with the αα-hub RCD1-RST. To maintain biological relevance, we developed an orthogonal evolutionary approach for the design of variants with varying amounts of structure. Biophysical analysis revealed a correlation between the amount of residual helical structure and binding affinity, manifested in altered complex lifetime due to changed dissociation rate constants. It also showed a correlation between helical structure in free and bound DREB2A variants. Overall, this study demonstrated how evolution can balance and fine-tune residual structure to regulate complexes in coupled folding and binding, potentially affecting transcription factor competition.

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“…Despite the flexible RCD1 binding SLiM, experiments on αα-hub binding show specific binding to RCD1 for DREB2 A over the structurally similar TAF4 αα-hub within the same species but much lower specificity when binding is examined for the orthologous coactivator from human (50x vs. 7x higher affinity, respectively), indicating that the SLiM has evolved to specifically bind RCD1 in its native context. [96] The authors suggest that small variations in the αα-hubs architecture result in different binding locations and modes of interaction for the partners, enabling some specificity despite the similar coactivator fold and residues. [92,96] These interactions are also distinguished by the contributions of enthalpy and entropy to binding with the specific interaction being more enthalpically favourable and less entropically favourable.…”

Section: Slim Specificitymentioning

confidence: 99%

“…[96] The authors suggest that small variations in the αα-hubs architecture result in different binding locations and modes of interaction for the partners, enabling some specificity despite the similar coactivator fold and residues. [92,96] These interactions are also distinguished by the contributions of enthalpy and entropy to binding with the specific interaction being more enthalpically favourable and less entropically favourable. Such differences in mode may increase the binding specificity differences in vivo where the crowded cellular milieu reduces the entropic space available and curtails the entropic benefit the non-specific binder has in vitro.…”

Section: Slim Specificitymentioning

confidence: 99%

Multifunctional Intrinsically Disordered Regions in Transcription Factors

Már

Nitsenko

Heidarsson

2023

Chemistry A European J

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Eukaryotic transcription factors (TFs) are the final integrators of a complex molecular feedback mechanism that interfaces with the genome, consolidating information for transcriptional regulation. TFs consist of both structured DNAbinding domains and long intrinsically disordered regions (IDRs) embedded with motifs linked to transcriptional control. It is now well established that the dynamic multifunctionality of IDRs is the basis for a wide spectrum of TF functions necessary to navigate and regulate the human genome. This review dissects the chemical features of TF IDRs that endow them with structural plasticity that is central to their functions in the nucleus. Sequence analysis of a set of over 1600 human TFs through AlphaFold was used to identify key features of their IDRs. Recent studies were then highlighted to illustrate IDR involvement in processes such as protein interactions, DNA binding and specificity, chromatin opening, and phase separation. To expand our understanding of TF functions, future directions are suggested for integrating experiments and simulations, from in vitro to living systems.

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αα-hub coregulator structure and flexibility determine transcription factor binding and selection in regulatory interactomes

Cited by 7 publications

References 77 publications

Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants

Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants

Evolutionary fine-tuning of residual helix structure in disordered proteins manifests in complex structure and lifetime

Multifunctional Intrinsically Disordered Regions in Transcription Factors

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